Immunopathological characteristics of immune reconstitution inflammatory syndrome caused by Mycobacterium parascrofulaceum infection in a patient with AIDS

Immune reconstitution inflammatory syndrome (IRIS) caused by mycobacterium in patients with AIDS is often experienced in clinical practice. There is, however, a paucity of data documenting the histopathological findings and the pathogenesis. We determined the immunopathological characteristics of IRIS associated with Mycobacterium parascrofulaceum infection in an AIDS patient. A patient presented with pulmonary lymphadenitis and involvement of the pulmonary lingular segment. Portions of the involved lymph nodes and lung were excised, and the immunological properties were analyzed by immunohistochemical assays. The histological characteristics of lymph nodes showed a caseous necrosis. Histopathologically, the pulmonary lesion was composed of exudative and proliferative lesions. CD4⁺, CD8⁺, CD57⁺, and CD25⁺/FoxP3⁺ cells were observed in both types of lesions. Clusters of CD20⁺ cells and GATA3⁺ cells were predominantly observed in exudative lesions, while T-bet⁺ cells were dominant in proliferative lesions. ROR-γ⁺ cells were also observed in exudative lesions. These results indicate that the cellular immunity to mycobacteria was recovering in the lung tissue. In M. parascrofulaceum pulmonary infection, the exudative lesion had characteristics of Th2 and Th17-type immunities. In contrast, the proliferative lesion had characteristics of Th-1 type immunity. Our data provide the first evidence to reveal the status of the axis of distinctive immunity in the process of granuloma formation caused by a mycobacterium-related infection.     

Intravenous immunoglobulin induces IgG internalization by tolerogenic myeloid dendritic cells that secrete IL-10 and expand Fc-specific regulatory T cells

Intravenous immunoglobulin (IVIG) is used as an immunomodulatory agent in many inflammatory conditions including Multisystem Inflammatory Syndrome-Children (MIS-C) and Kawasaki disease (KD). However, the exact mechanisms underlying its anti-inflammatory action are incompletely characterized. Here, we show that in KD, a pediatric acute vasculitis that affects the coronary arteries, IVIG induces a repertoire of natural Treg that recognize immunodominant peptides in the Fc heavy chain constant region. To address which antigen-presenting cell (APC) populations present Fc peptides to Treg, we studied the uptake of IgG by innate cells in subacute KD patients 2 weeks after IVIG and in children 1.6–14 years after KD. Healthy adults served as controls. IgG at high concentrations was internalized predominantly by two myeloid dendritic cell (DC) lineages, CD14⁺ cDC2 and ILT-4⁺ CD4⁺ tmDC mostly through Fcγ receptor (R) II and to a lesser extent FcγRIII. Following IgG internalization, these two DC lineages secreted IL-10 and presented processed Fc peptides to Treg. The validation of IVIG function in expanding Fc-specific Treg presented by CD14⁺ cDC2 and ILT-4⁺ CD4⁺ tmDC was addressed in a small cohort of patients with MIS-C. Taken together, these results suggest a novel immune regulatory function of IgG in activating tolerogenic innate cells and expanding Treg, which reveals an important anti-inflammatory mechanism of action of IVIG.     

Circulating cytotoxic immune components in dominant Charcot-Marie-Tooth syndrome

Activated T cells, measured repeatedly in the demyelinating peripheral neuropathy, Charcot-Marie-Tooth syndrome (CMT: hereditary motor sensory neuropathy), might participate in myelin loss by a destructive inflammatory autoimmune process. To explore this possibility, plasma proportions of hydroxyleukotrienes, their fatty acid precursor, arachidonic acid, and lymphocyte epitopes associated with immune cell activation expression were measured in 18 adults with dominant, Type I CMT. Compared to age-matched normal controls, CMT I patients showed eicosanoid-linked immunoactivation by an elevated content of 12-hydroxy-eicosatetraenoic acid (12-HETE) in parallel with a decreased plasma percentage of its fatty acid precursor, arachidonic acid. CMT patients also had increased numbers of peripheral lymphocytes expressing activation-related epitopes, CD25⁺, CD26⁺, CD4⁺, and CD4/CD45RO⁺ primed memory cells, with enhanced CD8⁺ cytotoxic cells and soluble CD8 protein content. Therefore, endogenously stimulated CMT I lymphocytes include functional cytotoxic cells which appear to deplete the plasma fatty acid precursor of prostenoid agents during the secretion of potentially destructive cytokines.     

Pediatric multisystem inflammatory syndrome associated with COVID-19: Insights in pathogenesis and clinical management

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a major challenge to be faced in recent years. While adults suffered the highest morbidity and mortality rates of coronavirus disease 2019, children were thought to be exclusively asymptomatic or to present with mild conditions. However, around April 2020, there was an outbreak of a new clinical syndrome related to SARS-CoV-2 in children - multisystemic inflammatory syndrome in children (MIS-C) - which comprises a severe and uncon-trolled hyperinflammatory response with multiorgan involvement. The Centers for Disease Control and Prevention considers a suspected case of MIS-C an individual aged < 21 years presenting with fever, high inflammatory markers levels, and evidence of clinically severe illness, with multisystem (> 2) organ involvement, no alternative plausible diagnoses, and positive for recent SARS-CoV-2 infection. Despite its severity, there are no definitive disease management guidelines for this condition. Conversely, the complex pathogenesis of MIS-C is still not completely understood, although it seems to rely upon immune dysregulation. Hence, in this study, we aim to bring together current evidence regarding the pathogenic mechanisms of MIS-C, clinical picture and management, in order to provide insights for clinical practice and implications for future research directions.     

Inflammation, T-Cell Phenotype, and Inflammatory Cytokines in Chronic Kidney Disease Patients Under Hemodialysis and its Relationship to Resistance to Recombinant Human Erythropoietin Therapy

Background Resistance to recombinant human erythropoietin (rhEPO) occurs in some chronic kidney disease (CKD) patients, which may be due to enhanced systemic inflammatory response and to the erythropoiesis-suppressing effect of pro-inflammatory cytokines, some of which are produced by T cells. Aim of study The aim of this study was to investigate the relationship between resistance to rhEPO therapy in hemodialysis CKD patients and inflammatory markers [C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (sIL2R), and serum albumin levels], blood cell counts, T-cell phenotype, cytokine production by T cells, and serum cytokine levels. Materials and Methods We studied 50 hemodialysis CKD patients, 25 responders and 25 nonresponders to rhEPO, and compared them to each other and with 25 healthy controls. When compared to controls, CKD patients showed increased serum levels of CRP, IL-6, and sIL2R and a T-cell lymphopenia, due to decreased numbers of both CD4⁺ and CD8⁺ T cells. T cells from CKD patients had an immunophenotype compatible with chronic T-cell stimulation as shown by the increased percentage of CD28⁻, CD57⁺, HLA-DR⁺, CD28⁻HLA-DR⁺, and CD57⁺ HLA-DR⁺ T cells and produce higher levels of IL-2, INF-γ, and TNF-α after short-term in vitro stimulation, although Th1 cytokines were not detectable in serum. Statistically significant differences were found between responders and nonresponders to rhEPO therapy for total lymphocyte and CD4⁺ T-lymphocyte counts, albumin (lower in nonresponders) and CRP (higher in nonresponders) levels. Conclusion CKD patients under hemodialysis present with raised inflammatory markers and decrease of total lymphocyte and CD4⁺ T-lymphocyte counts when compared with controls. Some of those markers are even further enhanced in nonresponders to rhEPO therapy patients, but resistance to this therapy cannot be justified by a Th1 polarized T-cell response.     

Activation or exhaustion of CD8+ T cells in patients with COVID-19

In addition to CD4⁺ T cells and neutralizing antibodies, CD8⁺ T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19), an ongoing pandemic disease. In patients with COVID-19, CD8⁺ T cells exhibiting activated phenotypes are commonly observed, although the absolute number of CD8⁺ T cells is decreased. In addition, several studies have reported an upregulation of inhibitory immune checkpoint receptors, such as PD-1, and the expression of exhaustion-associated gene signatures in CD8⁺ T cells from patients with COVID-19. However, whether CD8⁺ T cells are truly exhausted during COVID-19 has been a controversial issue. In the present review, we summarize the current understanding of CD8⁺ T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8⁺ T cells in the context of activation and exhaustion. We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8⁺ T cells and discuss long-term SARS-CoV-2-specific CD8⁺ T-cell memory.Keywords: CD8⁺ T cell, Activation, T-cell exhaustion, SARS-CoV-2, COVID-19Subject terms: Cellular immunity, Infection     

CD39 expression on Treg and Th17 cells is associated with metabolic factors in patients with type 2 diabetes

Th17 cells are involved in the pathogenesis of multiple inflammatory diseases such as type two diabetes (T2D). CD39⁺ Treg cells have been implicated as responsible for suppressing Th17 cells. The aim of this study was to evaluate the number and function of CD4⁺CD25^highCD39⁺ Treg and Th17 cells in peripheral blood mononuclear cells (PBMC) from T2D patients and healthy control subjects. The Th17 cells were detected in PBMC under culture with human anti-CD3/CD28 and PMA/ionomycin and the levels of IL-17 were assessed by ELISA and qPCR. The T2D patients with obesity showed significantly lower percentages of CD39⁺ Treg cells. A negative correlation between CD39⁺ Treg cells and weight, and body mass index was detected. In contrast, the low levels of CD4⁺IL-17⁺ cells in overweight and obese T2D patients showed a positive correlation with glucose and HbA1c. Additionally, we found a subpopulation of Th17 cells that express CD39 and were correlated with glucose and HbA1c. Our findings suggest that the expression of CD39 on Treg cells and also in CD4⁺IL-17⁺ cells from T2D patients is related to hyperglycemia as well as to overweight and obesity and therefore may participate as a modulator of the effector capacity of Th17 cells.     

Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

Vaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodent Plasmodium yoelii model. Protection is dependent on CD8⁺ T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8⁺ T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8⁺ T cell phenotype and demonstrated significant upregulation of CD11c on CD3⁺ CD8b⁺ T cells in the liver, spleen, and peripheral blood. CD11c⁺ CD8⁺ T cells are predominantly CD11a^hi CD44^hi CD62L⁻, indicative of antigen-experienced effector cells. Following in vitro restimulation with malaria-infected hepatocytes, CD11c⁺ CD8⁺ T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c⁻ CD8⁺ T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8⁺ T cells. Coculture of CD11c⁺, but not CD11c⁻, CD8⁺ T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8⁺ T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c⁺ CD8⁺ T cell response, but CD11c expression was lost as the CD8⁺ T cells entered the memory phase. Further analyses showed that CD11c⁺ CD8⁺ T cells are primarily KLRG1⁺ CD127⁻ terminal effectors, whereas all KLRG1⁻ CD127⁺ memory precursor effector cells are CD11c⁻ CD8⁺ T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.     

Differential Cytokine Expression and Regulatory Cells in Patients with Primary and Secondary Sjögren's Syndrome

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands. The aim of the study was to characterize and compare the presence of diverse cytokines and regulatory T and B cells in lip minor salivary gland (MSG) biopsies from patients with primary Sjögren's syndrome (pSS), secondary SS (sSS), and patients with connective tissue disease (CTD) without (w/o) SS. We included samples of MSG from 15 pSS, 24 sSS (six scleroderma, nine rheumatoid arthritis and nine lupus patients) and 15 patients with CTD w/o SS. Tissues were examined by an indirect immunoperoxidase technique (goat polyclonal anti‐human IL‐19, goat polyclonal anti‐human IL‐22 or mouse monoclonal anti‐human IL‐24). To determine the subpopulation of CD4⁺/IL‐17A⁺‐, CD4⁺/IL‐4⁺‐, CD4⁺/IFN‐?⁺‐expressing T cells, CD25⁺/Foxp3⁺ Treg cells and CD20⁺/IL‐10⁺‐producing B cell subset, a double‐staining procedure was performed. We estimated the mean percentage of positively staining cells in two fields per sample. CD4⁺/IFN‐?⁺, CD4⁺/IL‐4⁺ and IL‐22⁺ cell percentages were elevated in both SS varieties; however, the cells were more prevalent in pSS. Patients with pSS had a high number of CD4⁺/IL‐17A⁺ and IL‐19⁺ T cells and a lower percentage of IL‐24⁺ cells (P < 0.05). The Treg and IL‐10‐producing B cells were increased in pSS (P < 0.05). Concluding, in our patients, a pro‐inflammatory and regulatory balance coexists in SS, being both responses more intense in pSS. The explanation of these differences may be related to disease activity, disease duration and treatment.     

MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases

Th17 cells are a subset of CD4⁺ T cells characterized by production of IL-17 and are known to be key participants in inflammatory reactions and various autoimmune diseases. In this study we found that a subset of human CD4⁺ T cells expressing MCAM (CD146) have higher mRNA levels of RORC2, IL-23R, IL-26, IL-22, IL-17A, but not IFN-γ, compared to CD4⁺ T cell not expressing CD146. Upon TCR stimulation with CD3/CD28, CD4⁺CD146⁺ T cells secrete significantly more IL-17A, IL-6, and IL-8 than do CD4⁺CD146⁻ T cells. Low frequencies of CD4⁺CD146⁺ T cells are found in the circulation of healthy adults, but the frequency of these cells is significantly increased in the circulation of patients with inflammatory autoimmune diseases including Behcet’s, sarcoidosis and Crohn’s disease. Patterns of gene expression and cytokine secretion in these cells are similar in healthy and disease groups. In Crohn’s disease, the increase in CD4⁺CD146⁺ cells in the circulation correlates with disease severity scores. These data indicate that expression of CD146 on CD4⁺ T cells identifies a population of committed human Th17 cells. It is likely the expression of CD146, an endothelial adhesion molecule, facilitates adherence and migration of Th17 cells through the endothelium to sites of inflammation.     

Immune repertoire sequencing reveals an abnormal adaptive immune system in COVID-19 survivors

Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the adaptive immune system during acute infection. Still, it remains largely unclear whether the frequency and functions of T and B cells return to normal after the recovery of Coronavirus Disease 2019 (COVID-19). Here, we analyzed immune repertoires and SARS-CoV-2-specific neutralization antibodies in a prospective cohort of 40 COVID-19 survivors with a 6-month follow-up after hospital discharge. Immune repertoire sequencing revealed abnormal T- and B-cell expression and function with large T cell receptor/B cell receptor clones, decreased diversity, abnormal class-switch recombination, and somatic hypermutation. A decreased number of B cells but an increased proportion of CD19⁺CD138⁺ B cells were found in COVID-19 survivors. The proportion of CD4⁺ T cells, especially circulating follicular helper T (cTfh) cells, was increased, whereas the frequency of CD3⁺CD4⁻ T cells was decreased. SARS-CoV-2-specific neutralization IgG and IgM antibodies were identified in all survivors, especially those recorded with severe COVID-19 who showed a higher inhibition rate of neutralization antibodies. All severe cases complained of more than one COVID-19 sequelae after 6 months of recovery. Overall, our findings indicate that SARS-CoV-2-specific antibodies remain detectable even after 6 months of recovery. Because of their abnormal adaptive immune system with a low number of CD3⁺CD4⁻ T cells and high susceptibility to infections, COVID-19 patients might need more time and medical care to fully recover from immune abnormalities and tissue damage.     

Primed and naive helper T cells in labial glands from patients with Sjogren's syndrome

Summary This study has investigated the presence and distribution of B cells, T cells and T-cell subsets within labial glands of patients with primary Sjogren's syndrome (n=9) and secondary Sjogren's syndrome associated with rheumatoid arthritis (n=8) using a sequential double immunoperoxidase technique and true colour image analysis. The composition of the inflammatory infiltrates was similar in glands from both patient groups. B cells were normally present within large foci with few detected in diffuse infiltrates such that the ratio of TB cells in foci (2.41) was significantly lower than in diffuse infiltrates (7.31; P<0.001). In all infiltrates helper T cells (CD8^–, CD3⁺) predominated over suppressor/cytotoxic cells (CD8⁺, CD3⁺; 2.71). Analysis of primed (CD45RA^–, CD45RO⁺) and naive (CD45RA⁺, CD45RO^–) CD8^– T cells showed that the ratio of the primed to naive subset was significantly higher in focal (4.21) compared to diffuse (1.51;P< 0.001) areas of lymphoid infiltration. These results indicate that the focal lymphocytic infiltrates characteristic of Sjogren's syndrome contain B cells associated with a T-cell population consisting predominantly of primed CD8^– helper T cells. This latter population may be responsible for upregulating glandular B-cell activity in Sjogren's syndrome.     

The impact of intestinal resection on the immune function of short bowel syndrome patients

Short bowel syndrome (SBS) is characterized by a massive intestinal loss after surgery resection. Likewise, disturbances involving the intestine, which represents a complex immune environment, may result in breakdown of homeostasis and altered responses, thus leading to unpredictable clinical outcomes. However, the consequences of bowel resection were poorly investigated until now. Therefore, this study aimed to evaluate the immunological status of SBS-patients. For this purpose, ten subjects and nine healthy controls were evaluated. Along with some metabolic disturbances, the main results showed higher levels of the inflammatory cytokine IL-6 in plasma among SBS-patients. However, there were no differences in the frequency of CD3⁺, CD3⁺CD4⁺ or CD3⁺CD8⁺ T lymphocytes. An augmented frequency in CD4⁺ and CD8⁺ cells producing IFN-γ was also observed in peripheral blood mononuclear cells (PBMC), together with elevated percentage of CD4⁺ cells producing IL-10. No differences were observed in the frequency of total CD4⁺CD25⁻, CD4⁺CD25⁺ lymphocytes nor in the expression of FoxP3 or GITR. Nevertheless, SBS-patients showed higher frequency of the regulatory T cell population CD4⁺CD25⁺CD39⁺ cells in PBMC. In conclusion, these data pointed to SBS as an important disturbance that compromises not only the intestinal environment but also negatively influences systemic immune components.     

Inflammatory cells in minor salivary glands of patients with chronic hepatitis C: Immunophenotype,pattern of distribution,and comparison with liver samples

Objectives

To characterize the immunophenotype and the distribution of the inflammatory infiltrate (INF) in salivary glands (SG) of patients with chronic hepatitis C, comparing with laboratorial data (genotype, viral load, METAVIR, and HCV RNA in SG), and liver.

Methods

INF was classified as diffuse or focal. Immunohistochemistry for CD3, CD20, CD8, CD4, CD57, CD68, and S100 was performed in 61 SG and 59 livers.

Results

Diffuse INF was more common in SG than in liver. CD3⁺, CD20⁺, and CD8⁺ were the most frequent cells in both tissues, with few CD57⁺, CD68⁺, and S100⁺ cells. CD4⁺ cells were common in liver, but rare in SG. Liver presented higher indexes for all markers, except S100⁺ (p < 0.05). Higher CD3⁺, CD20⁺, and CD8⁺ (p < 0.05) were observed in SG with focal infiltrate than with diffuse infiltrate. In liver, CD20⁺ and CD3⁺ were higher in focal infiltrate, and CD68⁺ in diffuse infiltrate (p < 0.05). Comparisons with laboratorial data did not show statistical significance.

Conclusions

The INF in SG was mainly composed by T and B lymphocytes, mostly cytotoxic T cells. The glandular INF can present differences in composition according to its distribution. A more intense inflammation was observed in liver, but similar cell types were identified in SG, except for CD4⁺.     

Induction of contact-dependent CD8(+) regulatory T cells through stimulation with staphylococcal and streptococcal superantigens

The bacterial superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes are potent stimulators of polyclonal T-cell proliferation. They are the causes of toxic shock syndrome but also induce CD25⁺ FOXP3⁺ regulatory cells in the CD4 compartment. Several studies have recently described different forms of antigen-induced regulatory CD8⁺ T cells in the context of inflammatory diseases and chronic viral infections. In this paper we show that bacterial superantigens are potent inducers of human regulatory CD8⁺ T cells. We used four prototypic superantigens of S. aureus (toxic shock syndrome toxin-1 and staphylococcal enterotoxin A) and Str. pyogenes (streptococcal pyrogenic exotoxins A and K/L). At concentrations below 1 ng/ml each toxin triggers concentration-dependent T-cell receptor Vβ-specific expression of CD25 and FOXP3 on CD8⁺ T cells. This effect is independent of CD4⁺ T-cell help but requires antigen-presenting cells for maximum effect. The cells also express the activation/regulatory markers cytotoxic T-lymphocyte antigen-4 and glucocorticoid-induced tumour necrosis factor receptor-related protein and skin homing adhesins CD103 and cutaneous lymphocyte-associated antigen. Superantigen-induced CD25⁺ FOXP3⁺ CD8⁺ T cells were as potent as freshly prepared naturally occurring CD4⁺ regulatory T cells in suppressing proliferation of CD4⁺ CD25⁻ T cells in response to anti-CD3 stimulation. Although superantigen-induced CD8⁺ CD25⁺ FOXP3⁺ express interleukin-10 and interferon-γ their suppressive function is cell contact dependent. Our findings indicate that regulatory CD8⁺ T cells may be a feature of acute bacterial infections contributing to immune evasion by the microbe and disease pathogenesis. The presence and magnitude of regulatory CD8⁺ T-cell responses may represent a novel biomarker in such infections. Superantigen-induced regulatory CD8⁺ T cells also have therapeutic potential.     

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post‐transplant

Patients with recurrent miscarriage (RM) show up‐regulated cytotoxic natural killer (NK) cells that are suspected to play a causal role in abortion. In the present study, we investigated counter‐regulating inhibitory mechanisms and compared the results in RM patients with those of healthy controls (HC), patients with end‐stage renal disease (ESRD) and kidney transplant recipients late post‐transplant (TX). NK, NK T and T cell subsets were analysed in the peripheral blood of 31 RM, 14 female ESRD and nine female TX patients as well as 21 female HC using eight‐colour fluorescence flow cytometry. Compared with HC, RM patients showed significantly higher absolute numbers of CD56⁺ NK cells co‐expressing the phenotype interferon (IFN)‐γR⁺, IL‐4⁺, transforming growth factor (TGF)‐β⁺, IL‐4⁺ human leucocyte antigen D‐related (HLA‐DR)⁺, TGF‐β⁺HLA‐DR⁺, IL‐4⁺TGF‐β⁺, IL‐4⁺TGF‐β^–, IFN‐γ⁺ and/or IL‐10^–IFN‐γ⁺ (all P ≤ 0·01), more IL‐17⁺CD56^bright (P = 0·028) NK cells and more CD56^dimCD16⁺ NK cells co‐expressing IFN‐γR, IFN‐γ, IL‐4 and/or TGF‐β (all P ≤ 0·01). When the same cell subsets were analysed in ESRD or TX patients, cytokine‐producing NK cell subsets were not significantly different from those of HC. RM patients showed significantly higher absolute numbers of CD158a⁺, CD158b⁺, CD158a^–CD158e⁺ (all P < 0·05), NKG2D⁺NKG2A⁺, NKG2D ⁺NKG2A^–, NKG2D⁺ and/or NKG2A⁺ (all P ≤ 0·01) CD56⁺ NK cells and higher CD158a⁺, CD158b⁺ (all P < 0·05), NKG2D⁺ and/or NKG2A⁺ (all P < 0·01) CD56^dim+CD16⁺ NK cells than HC. In contrast, ESRD patients had normal and TX recipients had lower CD158a⁺ and NKG2D⁺NKG2A^–CD56⁺ NK cells and lower CD158a⁺CD56^dim+CD16⁺ NK cells (all P < 0·05) than HC. RM patients have abnormally high circulating NK cells expressing inhibitory cytokines and inhibitory surface receptors which might contribute to the pathogenesis of RM.     

IL‐18Rα‐deficient CD4+ T cells induce intestinal inflammation in the CD45RBhi transfer model of colitis despite impaired innate responsiveness

IL‐18 has been implicated in inflammatory bowel disease (IBD), however its role in the regulation of intestinal CD4⁺ T‐cell function remains unclear. Here we show that murine intestinal CD4⁺ T cells express high levels of IL‐18Rα and provide evidence that IL‐18Rα expression is induced on these cells subsequent to their entry into the intestinal mucosa. Using the CD45RB^hi T‐cell transfer colitis model, we show that IL‐18Rα is expressed on IFN‐γ⁺, IL‐17⁺, and IL‐17⁺IFN‐γ⁺ effector CD4⁺ T cells in the inflamed colonic lamina propria (cLP) and mesenteric lymph node (MLN) and is required for the optimal generation and/or maintenance of IFN‐γ‐producing cells in the cLP. In the steady state and during colitis, TCR‐independent cytokine‐induced IFN‐γ and IL‐17 production by intestinal CD4⁺ T cells was largely IL‐18Rα?dependent. Despite these findings however, IL‐18Rα?deficient CD4⁺ T cells induced comparable intestinal pathology to WT CD4⁺ T cells. These findings suggest that IL‐18‐dependent cytokine induced activation of CD4⁺ T cells is not critical for the development of T‐cell‐mediated colitis.     

Aging and human CD4 regulatory T cells

Alterations in immunity that occur with aging likely contribute to the development of infection, malignancy and inflammatory diseases. Naturally occurring CD4⁺ regulatory T cells (Treg) expressing high levels of CD25 and forkhead box P3 (FOXP3) are essential for regulating immune responses. Here we investigated the effect of aging on the number, phenotypes and function of CD4⁺ Treg in humans. The frequency and phenotypic characteristics of CD4⁺, FOXP3⁺ T cells as well as their capacity to suppress inflammatory cytokine production and proliferation of CD4⁺, CD25⁻ T cells (target cells) were comparable in young (age ≤40) and elderly (age ≥65) individuals. However, when CD4⁺, FOXP3⁺ Treg and CD4⁺, CD25⁻ T cells were co-cultured at a ratio of 1:1, the production of anti-inflammatory cytokine IL-10 from CD4⁺, CD25⁻ T cells was more potently suppressed in the elderly than in the young. This finding was not due to changes in CTLA-4 expression or apoptosis of CD4⁺, FOXP3⁺ Treg and CD4⁺, CD25⁻ T cells. Taken together, our observations suggest that aging may affect the capacity of CD4⁺, FOXP3⁺ T cells in regulating IL-10 production from target CD4⁺ T cells in humans although their other cellular characteristics remain unchanged.     

Endothelial glycocalyx degradation in multisystem inflammatory syndrome in children related to COVID-19

Journal of Molecular Medicine - Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection...